Process for the synthesis of perindopril and its pharmaceutically acceptable salts

Abstract

Process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.

1. A process for the synthesis of compounds of formula (I): 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof,
 wherein a compound of formula (II): 
 
       
         
           
           
               
               
           
         
       
       wherein Bn represents a benzyl group, is reacted
 with a compound of formula (III) having the S configuration: 
 
       
         
           
           
               
               
           
         
       
       wherein X represents a halogen atom and BOC represents a tert-butoxycarbonyl group, in the presence of a base,
 to yield, after deprotection of the amino function, a compound of formula (IV): 
 
       
         
           
           
               
               
           
         
       
       wherein Bn represents a benzyl group,
 which is reacted with ethyl 2-oxopentanoate under hydrogen pressure, in the presence of palladium-on-carbon, to yield the compound of formula (I). 
 
     
     
       2. The process of  claim 1 , wherein the base used for the reaction between the compounds of formula (II) and (III) is an organic amine selected from triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine, or a mineral base. 
     
     
       3. The process of  claim 2 , wherein the mineral base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3  and KHCO 3 . 
     
     
       4. The process of  claim 1 , wherein the hydrogenation reaction is carried out in an alcoholic solvent. 
     
     
       5. The process of  claim 1 , wherein the hydrogenation reaction is carried out under a pressure of from 1 to 5 bars. 
     
     
       6. The process of  claim 1 , wherein the hydrogenation reaction is carried out at a temperature of from 20 to 60° C. 
     
     
       7. The process of  claim 1  for the synthesis of perindopril in the form of its tertbutylamine salt.